Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation

Jason Gotlib, Caroline Berubé, Joseph D. Growney, Ching Cheng Chen, Tracy I. George, Christopher Williams, Tomohiro Kajiguchi, Jia Ruan, Stan L. Lilleberg, Jeffrey A. Durocher, Jack H. Lichy, Yanfeng Wang, Pamela S. Cohen, Daniel A. Arber, Michael C. Heinrich, Len Neckers, Stephen J. Galli, D. Gary Gilliland, Steven E. Coutré

    Research output: Contribution to journalArticle

    204 Scopus citations


    The majority of patients with systemic mast cell disease express the imatinib-resistant Asp816Val (D816V) mutation in the KIT receptor tyrosine kinase. Limited treatment options exist for aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL). We evaluated whether PKC412, a small-molecule inhibitor of KIT with a different chemical structure from imatinib, may have therapeutic use in advanced SM with the D816V KIT mutation. We treated a patient with MCL (with an associated myelodysplastic syndrome (MDS)/myeloproliferative disorder [MPD]) based on in vitro studies demonstrating that PKC412 could inhibit D816V KIT-transformed Ba/F3 cell growth with a 50% inhibitory concentration (IC50) of 30 nM to 40 nM. The patient exhibited a partial response with significant resolution of liver function abnormalities. In addition, PKC412 treatment resulted in a significant decline in the percentage of peripheral blood mast cells and serum histamine level and was associated with a decrease in KIT phosphorylation and D816V KIT mutation frequency. The patient died after 3 months of therapy due to progression of her MDS/MPD to acute myeloid leukemia (AML). This case indicates that KIT tyrosine kinase inhibition is a feasible approach in SM, but single-agent clinical efficacy may be limited by clonal evolution in the advanced leukemic phase of this disease.

    Original languageEnglish (US)
    Pages (from-to)2865-2870
    Number of pages6
    Issue number8
    StatePublished - Oct 1 2005


    ASJC Scopus subject areas

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

    Cite this

    Gotlib, J., Berubé, C., Growney, J. D., Chen, C. C., George, T. I., Williams, C., Kajiguchi, T., Ruan, J., Lilleberg, S. L., Durocher, J. A., Lichy, J. H., Wang, Y., Cohen, P. S., Arber, D. A., Heinrich, M. C., Neckers, L., Galli, S. J., Gilliland, D. G., & Coutré, S. E. (2005). Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood, 106(8), 2865-2870.